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WIREs Dev Biol
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Morphogen transport: theoretical and experimental controversies

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Abstract According to morphogen gradient theory, extracellular ligands produced from a localized source convey positional information to receiving cells by signaling in a concentration‐dependent manner. How do morphogens create concentration gradients to establish positional information in developing tissues? Surprisingly, the answer to this central question remains largely unknown. During development, a relatively small number of morphogens are reiteratively deployed to ensure normal embryogenesis and organogenesis. Thus, the intracellular processing and extracellular transport of morphogens are tightly regulated in a tissue‐specific manner. Over the past few decades, diverse experimental and theoretical approaches have led to numerous conflicting models for gradient formation. In this review, we summarize the experimental evidence for each model and discuss potential future directions for studies of morphogen gradients. WIREs Dev Biol 2015, 4:99–112. doi: 10.1002/wdev.167 This article is categorized under: Establishment of Spatial and Temporal Patterns > Gradients Signaling Pathways > Cell Fate Signaling Early Embryonic Development > Development to the Basic Body Plan
Two models of morphogen gradient formation. (a) Schematic illustrations of the accumulation and spreading models for the formation of morphogen gradients. (b–e) Examples of morphogen gradients established by accumulation (b and c) and spreading (d and e). (b and c) BMP morphogen gradients in Drosophila (b) and Xenopus (c) embyros. (d) DPP gradient in the developing Drosophila wing disc. (e) Shh gradient in the developing vertebrate limb bud. D: dorsal, V: ventral, A: anterior, P: posterior.
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Models of free diffusion and HSPG‐mediated transport. Models of free diffusion (a) and HSPG‐mediated transport (b) in morphogen gradient formation and experimental evidence for each. (a) Schematic illustration of the free diffusion (top). For free diffusion, only a small fraction of morphogen diffuses freely in the extracellular space. Spatial FRAP distinguishes between free diffusion and the other models (bottom, see the text for detail). The efficiency of florescence recovery between the two windows (entire region in the red dotted line and central region in the green dotted line) is compared. (b) Morphogens are transferred by extracellular HSPGs (top). Using mutant clones, morphogens are not able to form a gradient across cells lacking HPSGs (bottom).
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Planar transcytosis and cytonemes in gradient formation. Models of transcytosis (a) and cytoneme (b) mediated gradient formation and experimental evidence for each. (a) In planar transcytosis, morphogens are transferred by a sequence of endocytic and exocytic events (top). Morphogen transport is blocked when endocytosis is inhibited with a dynamin mutant (bottom, see the text for detail). (b) Cytonemes are proposed to transfer morphogens by a contact‐dependent mechanism (top). Ectopic morphogen expression induces the formation of cytonemes, which orient toward the ectopic morphogen source (middle). (c) Physical interaction between the morphogen expressing cell and cytonemes projected from the receiving cell.
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Morphogen production and gradient formation. (a) Source‐Sink model of morphogen gradient formation. (b) Misexpression of a morphogen (red dotted circle) results in ectopic gradient formation. The border between the morphogen expressing and receiving cells is indicated by the dotted line. (c) Differential regulation of TGF‐β/BMP, Hh, and Wnt morphogen production. Lipid and cholesterol modifications are indicated in red and blue, respectively. N and C represent N‐ and C‐terminal sides of the proteins.
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Establishment of Spatial and Temporal Patterns > Gradients
Signaling Pathways > Cell Fate Signaling
Early Embryonic Development > Development to the Basic Body Plan